Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems

Abstract

Summary:Because of the physiological nature of the bloodbrain barrier (BBB), transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent BBB permeation properties in many cases, and these discrepancies can be ascribed to the existence of multiple mechanisms of drug transport through the BBB. Molecular identification and functional analysis of influx transport proteins (from blood to brain) and efflux transport proteins (from brain to blood) have progressed rapidly. Therefore, the BBB is now considered to be a dynamic interface that controls the influx and efflux of a wide variety of substances, including endogenous nutrients and exogenous compounds such as drugs, to maintain a favorable environment for the CNS. This review focuses on the role of transport systems in the uptake of xenobiotics, including organic anionic/cationic and neutral drugs, across the BBB into the brain, as well as on strategies to increase drug delivery into the brain by blocking efflux transport protein function, or to reduce CNS side effects by modulating BBB transport processes.

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

“…Significant deviations from the above parabolic relationship have been found, which can be ascribed to the existence of multiple mechanisms of drug transport through the BBB [143] . There is clear evidence that the expression of active efflux pumps like the multidrug transporter P-glycoprotein (P-gP) at the BBB accounts for the poor permeability of certain drugs (see below).…”

“…Furthermore, a variety of nutrient transporters expressed at the BBB are able to transport certain xenobiotics and drugs [141,143] . Recently, it has been shown that the α4β2 …”

“…Accordingly, there is a rather small window of appropriate combinations of lipophilicity, molecular weight, and affi nity. Nevertheless, a nearly infi nite number of substances can theoretically be synthesized from basic organic elements within the restraints described above.Significant deviations from the above parabolic relationship have been found, which can be ascribed to the existence of multiple mechanisms of drug transport through the BBB [143] . There is clear evidence that the expression of active efflux pumps like the multidrug transporter P-glycoprotein (P-gP) at the BBB accounts for the poor permeability of certain drugs (see below).…”

“…Undoubtedly, P-gP is an important barrier to the entry of hydrophobic drugs into the brain [144] . Thus, proper prediction needs to consider active transport phenomena.Furthermore, a variety of nutrient transporters expressed at the BBB are able to transport certain xenobiotics and drugs [141,143] . Recently, it has been shown that the α4β2 …”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…E tápanyagok lehetnek cukrok, ketontestek, aminosavak, lipidek, vitaminok, ásványi sók, metabolikus prekurzorok, peptidek, fehérjék. Az agyi endothelsejtek számos ilyen transzportert expresszálnak: az aminosavtranszportban részt vevő SLC3 és SLC7 család tagjait (például L típusú aminosav-transzporter 1), a glükózt transzportáló SLC2-A2 (GLUT-1), a glutamáttranszportban részt vevő SLC1 család tagjait vagy az SLC15 (proton/oligopeptid transzporter -PEPT), az SLC16 (monokarboxilát-transzporter -MCT), az SLC21 (organikus aniontranszporterek -OAT), az SLC22 (organikus anion/kation transzporter -OCT), valamint az SLC44 (kolintranszporter -CTL) család tagjait [1].…”